Anti-Diabetic Therapies and Cancer: From Bench to Bedside

Abstract

Diabetes mellitus (DM) is a significant risk factor for various cancers, with the impact of anti-diabetic therapies on cancer progression differing across malignancies. Among these therapies, metformin has gained attention for its potential anti-cancer effects, primarily through modulation of the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway and the induction of autophagy. Beyond metformin, other conventional anti-diabetic treatments, such as insulin, sulfonylureas (SUs), pioglitazone, and dipeptidyl peptidase-4 (DPP-4) inhibitors, have also been examined for their roles in cancer biology, though findings are often inconclusive. More recently, novel medications, like glucagon-like peptide-1 (GLP-1) receptor agonists, dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, have revolutionized DM management by not only improving glycemic control but also delivering substantial cardiovascular and renal benefits. Given their diverse metabolic effects, including anti-obesogenic properties, these novel agents are now under meticulous investigation for their potential influence on tumorigenesis and cancer advancement. This review aims to offer a comprehensive exploration of the evolving landscape of glucose-lowering treatments and their implications in cancer biology. It critically evaluates experimental evidence surrounding the molecular mechanisms by which these medications may modulate oncogenic signaling pathways and reshape the tumor microenvironment (TME). Furthermore, it assesses translational research and clinical trials to gauge the practical relevance of these findings in real-world settings. Finally, it explores the potential of anti-diabetic medications as adjuncts in cancer treatment, particularly in enhancing the efficacy of chemotherapy, minimizing toxicity, and addressing resistance within the framework of immunotherapy.

Keywords: GLP-1 receptor agonists; SGLT-2 inhibitors; cancer; chronic low-grade inflammation; diabetes mellitus; doxorubicin-induced cardiomyopathy; immune check point inhibitors; metformin; tirzepatide; tumor microenvironment.

Figure 1

The impact of metformin on cancer-related signaling pathways via AMPK activation. AMPK activation by metformin disrupts key cancer-related signaling pathways, leading to inhibition of tumor growth and proliferation. AMPK deactivates the mTOR signaling pathway through phosphorylation and degradation mechanisms, inhibiting proteins such as p70S6K and 4E-BP1 involved in mRNA translation, thereby limiting cancer cell proliferation. Additionally, AMPK reduces phosphorylation of IRS-1, impairing signal transmission from IRs and IGF-1Rs, which disrupts the PI3K/Akt/mTOR signaling axis. In breast cancer, AMPK activation supports the survival of dormant ER⁺ tumor cells under low-estrogen conditions. In ovarian cancer, AMPK influences the AMPK/GSK3β axis, triggering cyclin D1 degradation through the ubiquitin-proteasome system, resulting in cell cycle arrest at the G1 phase. AMPK activation also promotes the production of ROS and induces apoptosis, which collectively hinder tumor growth [20,22,23,25,34,41]. Abbreviations: 4E-BP1: Eukaryotic translation initiation factor 4E-binding protein 1; Akt: Protein kinase B; AMPK: AMP-activated protein kinase; ER⁺: Estrogen receptor-positive; GSK3β: Glycogen synthase kinase 3 beta; IGF-1R: Insulin-like growth factor receptor; IR: Insulin receptor; IRS-1: Insulin receptor sub-strate-1; mTOR: Mammalian target of rapamycin; mRNA: Messenger RNA; p38MAPK: p38 mitogen-activated protein kinase; p70S6K: p70 ribosomal protein S6 kinase; PI3K: Phosphoinositide 3-kinase; Raptor: Regulatory-associated protein of mTOR; ROS: Reactive oxygen species; TSC2: Tuberous sclerosis complex 2; ULK1: Unc-51-like autophagy activating kinase 1. Created with www.BioRender.com.

Figure 2

Anti-tumor activity of SGLT-2 inhibitors in cancer models: insights from animal studies [123,124,125,127,130,133,136,137,138]. Abbreviations: AMPK: AMP-activated protein kinase; ATP: Adenosine triphosphate; CCL2: C-C motif chemokine ligand 2; CXCL8: C-X-C motif chemokine ligand 8; HIF-1α: Hypoxia-inducible factor 1-alpha; mTOR: Mammalian target of rapamycin; ODUT5: OTU deubiquitinase 5; PI3K: Phosphoinositide 3-kinase; SGLT-2: Sodium-glucose co-transporter 2; SIRT3: Sirtuin 3; YAP1: Yes-associated protein 1. Created with www.BioRender.com.

Figure 3

Schematic illustration of the diverse mechanisms through which anti-diabetic pharmacotherapy may affect tumor microenvironment dynamics. Metformin promotes the conversion of TAMs into an M1 phenotype, thereby enhancing anti-proliferative activity and inhibiting angiogenic processes. Pioglitazone modifies immune responses through the targeting of the IL-6/STAT3 signaling pathway, leading to increased activation of TILs, which are essential for recognizing and attacking tumor cells in the presence of mature dendritic cells. Additionally, canagliflozin reduces the release of the inflammatory chemokines CXCL8 and CCL2, which may limit the recruitment of immune cells while simultaneously increasing the chemokine CXCL10, ultimately inhibiting tumor angiogenesis. Conversely, DPP-4 inhibitors may promote metastatic processes by activating the ROS-mediated Nrf2/HO-1/NF-κB/NLRP3 signaling axis, resulting in elevated production of inflammatory cytokines, adhesion molecules, and angiogenic factors, including IL-6, ICAM-1, and VEGF [29,83,88,124]. Abbreviations: CANA: Canagliflozin; CCL2: C-C motif chemokine ligand 2; CXCL8: C-X-C motif chemokine ligand 8; CXCL10: C-X-C motif chemokine ligand 10; DCs: Dendritic cells; DPP-4: Dipeptidyl peptidase-4; HO-1: Heme oxygenase-1; ICAM-1: Intercellular adhesion molecule 1; IL-6: Interleukin 6; M1 phenotype: Macrophage 1 phenotype; M2 phenotype: Macrophage 2 phenotype; MTF: Metformin; NLRP3: NOD-like receptor family pyrin domain containing 3; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2: Nuclear factor erythroid 2-related factor 2; PIO: Pioglitazone; ROS: Reactive oxygen species; SAXA: Saxagliptin; STAT3: Signal transducer and activator of transcription 3; TILs: Tumor-infiltrating lymphocytes; TAMs: Tumor-associated mac-rophages; VEGF: Vascular endothelial growth factor. Created with www.BioRender.com.

Figure 4

Schematic presentation of signaling pathways influenced by anti-diabetic drugs to counteract doxorubicin cardiotoxicity. Metformin may enhance cardiac function by modulating autophagy and mitophagy pathways, which is evidenced by the normalization of autophagy markers such as beclin-1, LC3B-II, and p62. Liraglutide demonstrates the ability to reduce inflammation and apoptosis by decreasing the levels of pro-inflammatory cytokines (IL-6 and TNF-α), downregulating the pro-apoptotic caspase-3, and upregulating the anti-apoptotic protein Bcl-2. On the other hand, linagliptin exhibits anti-oxidant properties, potentially reducing oxidative stress through the reduction of GPx activity, thereby limiting ROS generation, decreasing lipid peroxidation, and mitigating MDA formation. This process preserves cellular integrity and improves myocardial fiber structure, which is crucial in alleviating DOX-induced cardiomyopathy. Lastly, empagliflozin is illustrated to potentially mitigate DOX-related cardiac injury by enhancing mitochondrial biogenesis through the activation of the AMPK/SIRT1/PGC-1α pathway. Additionally, it may reduce ferroptosis and enhance ketogenesis, contributing further to its cardioprotective effects [176,188,189,199,200,201]. Abbreviations: AMPK: AMP-activated protein kinase; Bcl-2: B cell lymphoma 2; DOX: Doxorubicin; EMPA: Empagliflozin; GPx: Glutathione peroxidase; IL-6: Interleukin 6; LC3B-II: Microtubule-associated protein 1A/1B light chain 3B, form II; LINA: Linagliptin; LIRA: Liraglutide: MDA: Malondialdehyde; MTF: Metformin; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; ROS: Reactive oxygen species; SIRT1: Sirtuin 1; TNF-α: Tumor necrosis factor-alpha. Created with www.BioRender.com.

Figure 5

Modulation of immune responses by anti-diabetic drugs in bolstering anti-PD-1 immunotherapy outcomes. Metformin enhances the infiltration of CD4⁺ T cells, crucial for initiating and sustaining anti-tumor immunity, while concurrently reducing the population of Tregs, which suppress immune responses within the TME. Moreover, metformin increases IL-17A levels and induces epigenetic modifications in Tregs, resulting in reductions in their immunosuppressive capabilities. By activating AMPK and triggering a downstream signaling cascade involving SIRT2, metformin promotes the downregulation of CCR8 on tumor-infiltrating Tregs. This downregulation decreases immune evasion and boosts anti-tumor responses, particularly when combined with PD-1 inhibitors. Pioglitazone and canagliflozin also contribute to improved ICI efficacy by promoting the degradation of PD-L1, a checkpoint protein that inhibits T cell activity. Pioglitazone acts as a PPAR-γ agonist, facilitating PD-L1 localization to lysosomes, while canagliflozin enhances PD-L1 recognition by the Cullin3SPOP E3 ligase for ubiquitination and proteasomal degradation. This degradation leads to increased infiltration of cytotoxic CD8⁺ T cells, thereby reinforcing the anti-tumor immune response. Additionally, liraglutide, through its GLP-1 receptor agonism, mitigates oxidative stress, resulting in reduced production of NETs, which can promote inflammation and tumor progression. By decreasing NET levels, liraglutide aids in alleviating tumor-promoting inflammation, thereby further enhancing the efficacy of ICIs [250,259,263,270]. Abbreviations: AMPK: AMP-activated protein kinase; Anti-PD-1: Anti-programmed cell death protein 1; CANA: Canagliflozin; CCR8: C-C chemokine receptor 8; CD4⁺ T cells: Cluster of differentiation 4 positive T cells; CD8⁺ T cells: Cluster of differentiation 8 positive T cells; dsDNA: Double-stranded deoxyribonucleic acid; IL-17A: Interleukin-17A; ICI: Immune checkpoint inhibitor PD-L1: Programmed death-ligand 1; LIRA: Liraglutide; MPO: Myeloperoxidase; MTF: Metformin; NETs: Neutrophil extracellular traps; PIO: Pioglitazone; PPAR-γ: Peroxisome proliferator-activated receptor gamma; ROS: Reactive oxygen species; SIRT2: Sirtuin 2; TME: Tumor microenvironment; Tregs: Regulatory T cells. Created with www.BioRender.com.